Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle

• Published in: Development (Cambridge) Vol. 135; no. 11; pp. 2043 - 2053
• Main Authors: Conti, Francesco J, Felder, Amanda, Monkley, Sue, Schwander, Martin, Wood, Malcolm R, Lieber, Richard, Critchley, David, Müller, Ulrich
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 01.06.2008
• Subjects: Actin Cytoskeleton - metabolism; Animals; Blotting, Western; Extracellular Matrix - metabolism; Immunohistochemistry; Integrin beta1 - metabolism; Integrins - metabolism; Mice; Mice, Knockout; Microscopy, Electron; Microscopy, Fluorescence; Models, Genetic; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - ultrastructure; Muscular Diseases - genetics; Muscular Diseases - metabolism; Muscular Diseases - pathology; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Reverse Transcriptase Polymerase Chain Reaction; Sarcolemma - metabolism; Talin - genetics; Talin - metabolism; Tendons - metabolism; Tendons - pathology; Tendons - ultrastructure
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.015818

The development and function of skeletal muscle depend on molecules that connect the muscle fiber cytoskeleton to the extracellular matrix (ECM).β 1 integrins are ECM receptors in skeletal muscle, and mutations that affect the α7β1 integrin cause myopathy in humans. In mice, β1 integrins control myoblast fusion, the assembly of the muscle fiber cytoskeleton, and the maintenance of myotendinous junctions (MTJs). The effector molecules that mediate β1 integrin functions in muscle are not known. Previous studies have shown that talin 1 controls the force-dependent assembly of integrin adhesion complexes and regulates the affinity of integrins for ligands. Here we show that talin 1 is essential in skeletal muscle for the maintenance of integrin attachment sites at MTJs. Mice with a skeletal muscle-specific ablation of the talin 1 gene suffer from a progressive myopathy. Surprisingly, myoblast fusion and the assembly of integrin-containing adhesion complexes at costameres and MTJs advance normally in the mutants. However, with progressive ageing, the muscle fiber cytoskeleton detaches from MTJs. Mechanical measurements on isolated muscles show defects in the ability of talin 1-deficient muscle to generate force. Collectively, our findings show that talin 1 is essential for providing mechanical stability to integrin-dependent adhesion complexes at MTJs, which is crucial for optimal force generation by skeletal muscle.